"Odours have a power of persuasion stronger than that of words, appearances, emotions, or will. The persuasive power of an odour cannot be fended off , it enters into us like breath into lungs, it fills us up, imbues us totally. There is no remedy for it"
-Patrick Süskind, quote from Perfume: The Story of a Murderer
Scientists have been searching for the basis of attraction for decades, and it appears that the way we smell may play a crucial role. But what exactly can our scent reveal? Recent studies suggest that our immune system may communicate its strength through olfactory cues, allowing potential partners to assess our genetic compatibility and potentially affecting the health of future generations.
What is the major histocompatibility complex and why does it matter in mate choice?
The immune system's recognition of foreign substances involves the major histocompatibility complex, a group of proteins present on the surface of cells in most animals. In humans, it is referred to as the human leukocyte antigen and is classified into two main types: class I and class II [1]. Class I is responsible for presenting organism's own antigens, which are its cells’ peptides that allow other immune cells to recognize them as their own. Class I can also present foreign antigens when it digests a pathogen it was infected by to take its peptide and present it to lymphocytes which will mark the cell for destruction, to prevent the spreading of the disease. MHC class II on the other hand, is present only on certain white blood cells that are involved in immune reactions. An immune cell will engulf a pathogen and digest it, later taking its peptide and presenting it in MHC class II to initiate an immune response. The term histocompatibility is derived from the Greek word histo for "tissue" and English "compatibility," as the complex was first discovered due to its importance in transplants in the 1950s when scientists experimented on mice conducting skin grafts, which involve the transplantation of skin from one part of the body to another or from one individual to another for various purposes. Through these experiments, researchers discovered the immune system's recognition of MHC molecules on foreign tissue. However, this name does not accurately describe the complex's physiological function.
Each gene in the MHC complex has a large number of alleles (different versions of a gene coding for the same characteristic), resulting in significant variation in MHC molecules among individuals. Previous studies suggest that the more different the alleles of the two parents are, the more beneficial it will be for the offspring, as it will give them immunity to a wider array of pathogens. Thus, we may seek out partners with a different set of alleles in their MHC when reproducing. However, recent research indicates that excessive MHC diversity may be associated with certain drawbacks, such as a higher risk of autoimmune disorders or a reduction in the ability to trigger an immune response. Therefore, a optimal diversity of the parents’ MHC is gaining support [2].
The mechanisms behind MHC mediated odour
If it is so important to find a partner with the right MHC for us, how is one’s MHC signaled? There is a wealth of research indicating that many animals use MHC-associated odour preferences in selecting mates. However, the mechanisms underlying the link between MHC and odour remain largely unclear and underexplored. In order to consider the potential role of MHC-mediated odour in mate preference, it is important to first understand how MHC can influence odour production. Some theories propose that MHC may have a direct effect on excreted products or an indirect effect by regulating the composition of odour-producing symbiotic bacteria through antigen-mediated elimination of certain species. As there is little research conducted on humans in this matter, we can look at how exactly this mechanism works in other animals. To investigate this topic further, a study was conducted on free-living adult song sparrows [3]. The research aimed to determine whether MHC influences odour production by affecting the community structure of odour-producing microbes, which can be shaped by MHC genotype, or by directly impacting the chemical composition of preen oil. Preen oil is a type of oil produced by a gland located near the tail feathers of birds and is used to maintain the health of their feathers [4]. It contains a mixture of organic compounds that help to waterproof and condition the feathers, as well as protect them from harmful bacteria and other microorganisms. In addition to its functional properties, preen oil may also play a role in social communication among birds, as some species use it to signal their dominance or attract potential mates. The researchers sampled blood and preen oil from 43 adult song sparrows. They characterized each bird’s MHC genotype, preen gland microbial communities, and preen oil chemistry. The results showed that birds with more similar MHC also had more similar preen gland microbiota, although birds with similar microbiota did not always have a similar chemical composition of preen oil. Nevertheless, pairs of individuals that were more similar at MHC class II also had more similar preen oil chemistry. The study suggests that MHC may affect host odour both directly (if MHC molecules or antigens that bind to them are odorous and excreted through urine or sweat) and indirectly (via microbes). The song sparrows in the study preferred the preen oil scent of MHC-dissimilar and MHC-diverse potential mates, and the researchers hypothesize that MHC can affect preen gland microbial communities, which in turn influences preen oil composition. These findings enhance our understanding of the complex relationship between MHC and odour, shedding light on the mechanisms underlying MHC-mediated odour and its potential role in mate choice.
After gaining a better understanding of how scent is formed in birds, it is crucial to explore the mechanisms behind odour production in humans. The majority of human body smell is emitted from the axillary region (commonly known as the underarm), which is home to different glands and bacteria [5]. These glands secrete precursor molecules that are odourless but bacterial enzymes convert them into volatile compounds that give off an odour. Therefore, human odour is the product of a complex interplay between the person’s secreted precursor molecules and the microbiome that produces the final odorous compounds. However, it is important to note that no association has been found between odorous carboxylic acid patterns (organic compoounds that produce a scent) and genes located in the human leukocyte antigens.
o we really use it?
While older studies have suggested that MHC plays a role in human odour and mate preferences, recent research contradicts this theory. In a seminal 1995 study, 121 men and women rated the odours of six T-shirts worn by four men and two women, and the results showed that women rated more highly the pleasantness of the scent when theirs MHC and that of the men that wore the T-shirts were more dissimilar [6]. The results differed for women that were using contraceptives. The study has garnered significant interest and has been cited 1935 times since. However, subsequent research has proven this theory to be incorrect. Researchers have shown that HLA-identical twins do not necessarily produce similar patterns of released odorants, and the T-shirt study has not been replicated on a larger scale [7]. Furthermore, no compelling analytical evidence has been presented to support a connection between body aromas and HLA. Given what is known about the binding requirements of HLA proteins, it is unlikely that they would bind to odorant precursors. Recent meta-analysis have found no significant correlation between MHC similarity and odour preferences, further calling into question the initial findings. The study suggests that publication bias may have influenced previous findings, underscoring the need for more research in this area. Current knowledge on the topic of MHC-associated odour preferences in humans remains limited, emphasising the importance of conducting further studies on populations of non-European descent, especially those with high levels of inbreeding.
Can animals recognize the dissimilarity?
Previously, we discussed how the MHC affects preen gland composition and odour producing microbes in birds, but how does it impact mate choice? While evidence supports the role of MHC in bird scents, it is still uncertain whether it plays a significant role as a social signal. A recent review of 577 publications from 2021 suggests that MHC cannot mediate social odour via microbiota, and none of the studies reviewed discussing MHC effects on odour showed it to be a social signal [8]. The review also mentions a study showing that there was no relation between MHC diversity and microbial diversity, which supports the hypothesis that a diverse MHC genotype causes elimination of more microbiota species. This raises questions about how females can deduce MHC diversity, as it would require to recognize the odour of all microorganisms and determine their absence. This raises questions about the use of MHC-mediated odour in mate choice.
Despite this, several recent studies suggest that birds can recognize MHC diversity and dissimilarity using odour cues. A study on gull species tested this hypothesis by placing male scent samples on the edge of a nest bowl from 43 incubating males and testing 52 incubating females to see their behavioural response to different samples [9]. The results showed that females took more time to peck at the odour sample when the male had a diverse MHC and less time to peck at an odour sample from a male with a dissimilar MHC to hers. The study concluded that this cannot be interpreted as a preference, but it shows that the birds used scent cues to recognize MHC-II diversity and MHC-II dissimilarity, undermining the previous study that questioned the ability of birds to recognize MHC diversity.
Possible different social odour cues – case study on fish
It is also important to point out that there are other olfactory cues that may be involved in mate choice. A study on three-spined sticklebacks aimed to investigate the function of MHC in mate selection, in contrast to other social scents [10]. The results demonstrated that the distinctiveness of MHC lies in its capability to transmit individual-specific information. The researchers employed a two-armed flow channel to expose female fish to male odour.
Initially, they tested the ability of females to react to the male validation factor (MVF) in the absence of MHC signals. The aim was to determine whether stickleback populations, which have been separated for thousands of years (becoming genetically isolated), have developed such unique MVF that females only respond to MVF generated by males from their own population. The MVF is necessary for females to differentiate between plain water and water containing MHC peptides, which enables them to recognize their own species. However, it does not contribute to population-specific mate selection since it only aids in species identification, preventing accidental interspecies hybridization.
To conduct the study, Gahr, Boehm, and Milinski took advantage of the fact that males do not release MHC signals until after completing their nest. Females followed the male's "zig-zag" courtship dance to his nest and evaluated the smell signal emanating from the nest owner's MHC profile by sniffing at the entrance of the nest. The male's fanning activity caused the scent to leave the nest and present MHC peptides to the female.
The researchers discovered that the MVF is evolutionarily conserved (remains unchanged over a period of time) since females responded to males from different populations. During the breeding season, when other fish may also engage in MHC-based mate selection, the MVF enables females to determine whether an MHC signal is originating from their own species, which is critical. Moreover, the MVF lacks population-specific features, implying that information about populations or individuals is signaled mostly by the MHC.
In conclusion, there is a significant number of research and data suggesting that the way we smell can signal important information about our immune system, influencing our choice of partner and potentially affecting the health of future generations. Nevertheless, despite these findings, the mechanisms behind this phenomenon and its precise implications for mate choice remain largely unresolved. Further investigation is required to fully comprehend the complexities of this fascinating topic.
Bibliography:
[1] Encyclopædia Britannica, inc. (2023). Major histocompatibility complex. Encyclopædia Britannica.https://www.britannica.com/science/major-histocompatibility-complex
[2] Pineaux, M., Blanchard, P., Ribeiro, L., Hatch, S. A., & Leclaire, S. (2023). A gull species recognizes MHC-II diversity and dissimilarity using odor cues. HAL archives-ouvertes. hal-03918940v3.
[3] Grieves, L. A., Gloor, G. B., Bernards, M. A., & MacDougall-Shackleton, E. A. (2021). Preen gland microbiota covary with major histocompatibility complex genotype in a songbird. Royal Society Open Science, 8(10), 210936.https://doi.org/10.1098/rsos.210936
[4] Dove, C. J. (2000). Preen gland secretions of seabirds: Compositional variation and neural control. Acta Zoologica Sinica, 46(Supplement), 113-116.
[5] Natsch, A., & Emter, R. (2020). The specific biochemistry of human axilla odour formation viewed in an evolutionary context. Philosophical Transactions of the Royal Society B: Biological Sciences, 375(1790), 20190269.https://doi.org/10.1098/rstb.2019.0269
[6] Wedekind, C., Seebeck, T., Bettens, F., & Paepke, A. J. (1995). MHC-dependent mate preferences in humans. Proceedings of the Royal Society of London Series B: Biological Sciences, 260(1359), 245–249. https://doi.org/10.1098/rspb.1995.0087 [
7] Havlíček, J., Winternitz, J., & Roberts, S. C. (2020). Major histocompatibility complex-associated odour preferences and human mate choice: Near and far horizons. Philosophical Transactions of the Royal Society B: Biological Sciences, 375(1800), 20190260. https://doi.org/10.1098/rstb.2019.0260
[8] Milinski, M. (2021). MHC mediates social odour via microbiota—it cannot work: A comment on Schubert et al. Behavioral Ecology, 32(3), 374–375. https://doi.org/10.1093/beheco/arab017
[9] Pineaux, M., Blanchard, P., Ribeiro, L., Hatch, S. A., & Leclaire, S. (2023). A gull species recognizes MHC-II diversity and dissimilarity using odor cues. HAL archives-ouvertes. hal-03918940v3.
[10] Gahr, C. L., Boehm, T., & Milinski, M. (2020). Male validation factor for three-spined stickleback (Gasterosteus aculeatus) mate choice likely evolutionarily conserved since 50 Thousand Years. Ethology Ecology & Evolution, 33(1), 25–36.https://doi.org/10.1080/03949370.2020.1789748